Method of treating arthritic disease

ABSTRACT

This disclosure describes compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease and the methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith, the active ingredients of said compositions of matter being certain 2,4,6-tris(substituted-amino)-s-triazines.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our application Ser. No.17,796, filed Mar. 5, 1979, now U.S. Pat. No. 4,261,892, which is acontinuation-in-part of our abandoned application Ser. No. 895,572,filed Apr. 12, 1978.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel compositions of matter useful asanti-inflammatory agents and as inhibitors of the progressive jointdeterioration characteristic of arthritic disease. More particularly, itrelates to therapeutic compositions containing certain N₂, N₄, N₆-tris(substituted)melamines which meliorate inflammation and inhibitarthritic joint deterioration in mammals. The invention includes the newcompositions of matter and the methods of meliorating inflammation andof inhibiting joint deterioration in mammals therewith. The activeingredients of the novel compositions of this invention may berepresented by the following structural formula: ##STR1## wherein R₁ isalkylamino having from 4 to 8 carbon atoms, inclusive, 1-adamantylamino,2-adamantylamino, exo[2.2.1]norbornylamino or endo[2.2.1]norbornylamino;R₂ is 1-adamantylamino, 2-adamantylamino, exo[2.2.1]norbornylamino orendo[2.2.1]norobornylamino; R₃ is hydrogen or alkyl having from 1 to 4carbon atoms, inclusive; R₄ is 2-[2-pyridyl]ethyl, alkyl having from 4to 8 carbon atoms, inclusive, phenyl, monohalo(F, Cl, Br)phenyl,1-adamantyl, 2-adamantyl, exo[2.2.1]norbornyl, endo[2.2.1]norbornyl or amonovalent moiety of the formula: ##STR2## wherein Q is a divalentmoiety of the formulae: ##STR3## R₅ is alkyl having up to 4 carbonatoms, R₆ is alkyl having up to 4 carbon atoms, and R₅ and R₆ takentogether with their associated N(itrogen) is piperidino, morpholino,pyrrolidino or thiomorpholino with the proviso that when R₄ is alkyl,adamantyl or norbornyl then R₃ must be hydrogen; and R₃ and R₄ takentogether with their associated N(itrogen) is pyrrolidino, piperidino,hexamethyleneimino, heptamethyleneimino or a monovalent moiety of theformula: ##STR4## wherein R is hydrogen, alkyl having up to 4 carbonatoms, phenyl, p-methoxyphenyl or carboalkoxy having up to 4 carbonatoms.

DETAILED DESCRIPTION OF THE INVENTION

The active compounds of the present invention are obtainable ascrystalline materials having characteristic melting points andabsorption spectra. They are appreciably soluble in many organicsolvents such as lower alkanols, acetone, ethyl acetate, and the like,but are generally insoluble in water. These compounds are capable offorming acid-addition and quaternary ammonium salts with a variety oforganic and inorganic salt-forming reagents when the substituent --NR₃R₄ contains a basic nitrogen atom. Thus, acid-addition salts, formed byadmixture of the organic free base with an equivalent of an acid,suitably in a neutral solvent, are formed with such acids as sulforicphosphoric, hydrochloric, hydrobromic, citric, tartaric, acetic, andrelated acids. In like manner, quaternary ammonium salts may be formedby reaction of the free bases with an equivalent of a variety of organicesters of sulfuric, hydrohalic and aromatic sulfonic acids. The organicreagents employed for quaternary ammonium salt formation are preferablylower alkyl halides. The acid-addition and quaternary ammonium salts ofthe active compounds of the present invention are, in general,crystalline solids relatively soluble in water, methanol and ethanol butrelatively insoluble in non-polar organic solvents such as diethylether, benzene, toluene, and the like. For purposes of this invention,the free bases are equivalent to their non-toxic acid-addition andquaternary ammonium salts.

The N₂, N₄, N₆ -tris(substituted)melamines of the novel compositions ofthe present invention may be readily prepared from cyanuric chloride (I)as set forth in the following reaction scheme: ##STR5## wherein R₁, R₂,R₃ and R₄ are as hereinabove defined. In accordance with the abovereaction scheme, cyanuric chloride (I) is reacted with one molecularequivalent of an amine of the formula R₁ H to provide the corresponding2-(substituted-amino)-4,6-dichloro-s-triazine (II). Treatment of (II)with one molecular equivalent of an amine of the formula R₂ H thenprovides the corresponding2-chloro-4,6-bis(substituted-amino)-s-triazine (III). Treatment of thelatter intermediate with an amine of the formula: ##STR6## wherein R₃and R₄ are as hereinabove defined then provides the active compounds(IV) of the present invention. The above reactions may be carried out inan inert solvent such as soluene or xylene for a period of time of fromabout 3 hours to 24 hours or more at temperatures ranging from about 25°C. to about 200° C. In addition, α-pyridone may be employed as catalystin solvents or as a reaction medium. Variation in the reaction time andtemperature is dependent upon the structure of the amine reagents; andan acid scavenger such as sodium bicarbonate, soda ash, or a tertiaryamine such as diisopropylethylamine should be employed to take up thehydrochloric acid produced in the reaction. In those cases where anexcess of amine may be used, then an acid scavenger and/or an inertsolvent may be dispensed with. Where R₁ and R₂ are the same, thentreatment of (I) with two molecular equivalents of amine provides theintermediate (III) directly.

The active compounds of the present invention have been found to behighly useful for meliorating inflammation and associated jointdeterioration in mammals when administered in amounts ranging from aboutone milligram to about 250 mg. per kilogram of body weight per day. Apreferred dosage regimen for optimum results would be from about 5 mg.to about 100 mg. per kilogram of body weight per day, and such dosageunits are employed that a total of from about 0.35 gm. to about 7.0 gm.of the active ingredient for a subject of about 70 kg. of body weightare administered in a 24 hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. A decided practical advantage of this invention is that theactive ingredient may be administered in any convenient manner such asby the oral, intravenous, intramuscular, topical, or subcutaneousroutes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatime,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weights of from about 200to 1500. Although the amount of active compound dissolved in the abovevehicle may vary from 0.10% to 10.0% by weight, it is preferred that theamount of active compound employed be from about 3.0% to about 9.0% byweight. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride, phenylmercuric nitrate, benzalkonium chloride, phenethyl alcohol,P-chlorophenyl-α-glycerol ether, methyl and propyl parabens, andthimerosal. As a practical matter it is also convenient to employantioxidants. Suitable antioxidants include, for example, sodiumbisulfite, sodium metabisulfits, and sodium formaldehyde sulfoxylate.Generally, from about 0.05% to about 0.2% concentrations of antioxidantare employed.

For intramuscular injection, the preferred concentration of activecompound is 0.25 to 0.50 mg./ml. of the finished compositions. Theseactive compounds are equally adapted to intravenous administration whendiluted with water or diluents employed in intravenous therapy such asisotonic glucose in appropriate quantities. For intravenous use, initialconcentrations down to about 0.05 to 0.25 mg./ml. of active compound aresatisfactory.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablers, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of tablers, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active ingredient in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 50 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

Adjuvant-induced experimental polyarthritis is a specific systemicdisease of the rat which shares interesting similarities with rheumatoidarthritis. Specifically, the histology of the two diseases bears aremarkable resemblance as shown by C. M. Pearson et al., Am. J. Pathol.42, 73 (1963). E. M. Glenn, Am. J. Vet. Res. 27 (116), 339 (1966) hasclassified adjuvant-induced polyarthritis as a crippling and permanentdeformity resulting from diffuse connective tissue involvement aroundcertain susceptible joints in the rat. Zahiri et al., Can. Med. Ass. J.101, 269 (1969) have shown that the fusiform swelling of the distaljoints is associated with edema, congestion and synovitis includingpannus formation, all of which precede the ultimate destruction of boneand cartilage. Furthermore, Zahiri et al. indicate that the cartilagedestruction in the joint is due to an invasive pannus which originatesin the marginal synovium and extends across the articular surface toerode it. When non-steroidal, anti-inflammatory agents such asindomethacin inhibit arthritic paw swelling, which is composed ofinflammatory cell infiltrates, they have also been shown to preventjoint and bone deterioration. See S. Wong et al., J. Pharm. & Exptl.Ther. 185, 127 (1973) and G. R. Bobalick et al., Agents & Actions 4, 364(1974). The most pertinent reference showing the relationship betweenarthritis and joint deterioration is an X-ray analysis of adjuvantarthritis in the rat by Blackham et al., Agents & Actions 7, 145 (1977).In a similar manner, inhibition of the progress of arthritis in paws ofrats treated with the compounds of this invention also lessensassociated joint deterioration.

The following test shows the activity of the compounds of this inventionagainst chronic inflammation in adjuvant-induced arthritis which isaccompanied by joint destruction. Groups of three Royal Hart, Wistarstrain rats weighing 200±10 grams each were injected intradermally inthe right hind paw with Freund's adjuvant (dried human tubercle bacilliin a mineral oil behicle) at a dose of 2 mg./kg. of body weight. Testcompounds were administered orally in a 1.5% starch vehicle at variousdoses once daily on days 0 through 13 post challenge. Control rats weretreated in a similar manner, but given only starch vehicle. On the 14thand 21st day post challenge the diameter of the injected paw (primarylesion) was measured by micrometer caliper. The volume of inflamed pawswere estimated from these measurements and the results are expressed aspercent inhibition of swelling as compared to controls. At the sametime, the other inflamed sites, such as ears, paws and tail (secondarylesions) were observed and each rat was graded as to degree ofinflammation and swelling present. The grading is based on a scale of 0to 24 where 0 represents a complete absence of induced arthritic nodulesand 24 represents the maximum degree of inflammation. The mean grade foreach treated group is calculated and the effects of each compound areexpressed as percent inhibition of the control grade. Table I belowrecords the results of tests conducted with the active compounds of thisinvention and known anti-inflammatory agents. The active compounds ofthis invention appear to suppress the progression of the arthritis andassociated joint deterioration.

                                      TABLE I                                     __________________________________________________________________________    The Effect of Anti-Inflammatory Agents on Adjuvant Arthritis In Rats                                              % Inhibition                                                                          % Inhibition of                                 Oral Dose     Mean Weight                                                                           of Swelling                                                                           Control Grade                                   mg./kg. of                                                                          Dead/Treated                                                                          Gain (grams)                                                                          (primary lesion)                                                                      (secondary lesion)                Compound      Body Wgt.                                                                           at 21 Days                                                                            Day 14                                                                            Day 21                                                                            Day 14                                                                            Day 21                                                                            Day 14                                                                             Day 21                       __________________________________________________________________________    Normal rats   --     8/186  77  112 --  --  --   --                           Adjuvant Controls                                                                           --    56/630  36  31   0   0   0    0                           N.sup.2 --(1-adamantyl)-N.sup.4,                                                            50    1/12    94  89  47  17  --   --                           N.sup.6 --bis(1,1,2,2-tetramethyl-                                            propyl)melamine                                                               N.sup.2 --(2-adamantyl)-N.sup.4,                                                            50    1/3     148 181 79  83  --   --                           N.sup.6 --bis(1,1,2,2-tetramethyl-                                            propyl)melamine                                                               N.sup.2 --(exo[2.2.1]norbornyl)-                                                            50    0/3     97  93  49  24  --   --                           N.sup.4,N.sup.6 --bis(1,1,2,2-tetra-                                          methylpropyl)melamine                                                         Indomethacin  2     8/57    68  68  51  24  38   25                                         1     9/54    63  65  46  19  34   20                                         0.5   5/54    53  51  40  20  25   17                                         0.25  0/9     51  57  30   4  22    4                           Aspirin       400   18/57   41  55  73  48  58   45                                         200   10/66   40  44  48  27  26   17                                         100   18/63   48  53  36  13  19    8                                         50    2/21    56  44  23   3  12    9                           Phenylbutazone                                                                              150   2/27    40  50  75  44  54   31                                         75    2/39    51  50  62  28  27   15                                         37.5  5/39    53  53  56  14  18   13                                         18.8  2/21    50  45  31   7   4    8                           __________________________________________________________________________

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation of 50 mg. Tablets

    ______________________________________                                        Per Tablet              Per 10,000 Tablets                                    ______________________________________                                        0.050 gm.  2-(1-adamantylamino)-4,6-                                                                      500     gm.                                                  bis(1,1,2,2-tetramethyl-                                                      butylamino)-s-triazine                                             0.080 gm.  Lactose          800     gm.                                       0.010 gm.  Corn Starch (for mix)                                                                          100     gm.                                       0.008 gm.  Corn Starch (for paste)                                                                        75      gm.                                       0.148 gm.                   1475    gm.                                       0.002 gm.  Magnesium Stearate (1%)                                                                        15      gm.                                       0.150 gm.                   1490    gm.                                       ______________________________________                                    

The2-(1-adamantylamino)-4,6-bis(1,1,2,2-tetramethylbutylamino)-s-triazine,lactose and corn starch (for mix) are blended together. The corn starch(for paste) is suspended in 600 ml. of water and heated with stirring toform a paste. This paste is then used to granulate the mixed powders.Additional water is used if necessary. The wet granules are passedthrough a No. 8 hand screen and dried at 120° F. The dry granules arethen passed through a No. 16 screen. The mixture is lubricated with 1%magnesium stearate and compressed into tablers in a suitable tabletingmachine.

EXAMPLE 2 Preparation of Oral Suspension

    ______________________________________                                        Ingredient              Amount                                                ______________________________________                                        2-(2-adamantylamino)-4,6-bis(1,1,3-                                                                   500    mg.                                            trimethylbutylamino)-s-triazine                                               Sorbitol solution (70% N.F.)                                                                          40     ml.                                            Sodium benzoate         150    mg.                                            Saccharin               10     mg.                                            Red dye                 10     mg.                                            Cherry flavor           50     mg.                                            Distilled water gs ad   100    ml.                                            ______________________________________                                    

The sorbitol solution is added to 40 ml. of distilled water and the2-(2-adamantylamino)-4,6-bis(1,1,3-trimethylbutylamino)-s-triazine issuspended therein. The succharin, sodium benzoate, flavor and dye areadded and dissolved. The solume is adjusted to 100 ml. with distilledwater. Each ml. of syrup contains 5 mg. of2-(2-adamantylamino)-4,6-bis(1,1,3-trimethylbutylamino)s-triazine.

EXAMPLE 3 Preparation of Parenteral Solution

In a solution of 700 ml. of propylene glycol and 200 ml. of water forinjection is suspended 20.0 grams of N² -(exo[2.2.1]norbornyl)-N⁴,N⁶-bis(1,1,4-trimethylpentyl)melamine with stirring. After suspension iscomplete the pH is adjusted to 5.5 with hydrochloric acid and the volumeis made up to 1000 ml. with water for injection. The formulation issterilized, filled into 5.0 ml. ampoules each containing 2.0 ml.(representing 40 mg. of drug) and sealed under nitrogen.

EXAMPLE 4 Preparation of Topical Cream

    ______________________________________                                        Ingredient                Amount                                              ______________________________________                                        2-(endo[2.2.1]norbornylamino)-4,6-bis(1,1,2,2-                                                          1.0%                                                tetramethylbutylamino)-s-triazine                                             Ethoxylated stearyl alcohol                                                                             10.0%                                               Benzyl alcohol            0.9%                                                Isopropyl palmitate       5.0%                                                Glycerin                  5.0%                                                Sorbitol solution (USP)   5.0%                                                Lactic acid gs to pH 4.0-5.0                                                  Water gs ad               100.00%                                             ______________________________________                                    

The ethoxylated stearyl alcohol and isopropyl palmitate are heated toliquifying temperature. About 95% of the total volume of water is placedin a separate container followed by the flycerin and sorbitol solution.This aqueous mixture is brought to a boil and then cooled to 60°-75° C.The2-(endo[2.2.1]norbornylamino)-4,6-bis(1,1,2.2-tetramethylbutylamino)-s-triazineadjusted to 4.0-5.0 with lactic acid. The batch is cooled with minimumagitation until the cream sets in its final form.

EXAMPLE 5 Preparation of Injectable Depo Suspension

    ______________________________________                                        Ingredient                 % W/V                                              ______________________________________                                        N.sup.2 --(1-adamantyl)-N.sup.4, N.sup.6 --bis(1,1,2,2-tetramethyl-                                      0.05-5                                             butyl)melamine                                                                Polysorbate 80 USP         0.2                                                Polyethylene glycol 4000 USP                                                                             3.0                                                Sodium chloride USP        0.8                                                Benzyl alcohol N.F.        0.9                                                HCL to pH 6-8              qs                                                 Water for injection qs ad  100.0                                              ______________________________________                                    

EXAMPLE 6 Preparation of N² -1-adamantyl-N⁴,N⁶-bis(1,1,2,2-tetramethylpropyl)melamine

Seven grams (0.02 mole) of2-chloro-4,6-bis[1,1,2,2-tetramethylpropyl)amino]-s-triazine is groundup in a mortar and 24 g. (0.16 mole) of 1-adamantylamine is intimatelymixed, placed in a glass liner in a bomb and then heated in an oil bathmaintained at 210°-220° C. for 20 hours. After cooling, the contents ofthe bomb are rinsed with chloroform and water into a flask and 50 ml. of10N NaOH is added. The solution is then evaporated in vacuo and theaqueous solution remaining is extracted with chloroform. The combinedchloroform extracts are washed with water, dried over magnesium sulfate,filtered through Magnesol® and the Magnesol® washed with chloroform.Removal of solvent in vacuo, addition of toluene and re-evaporation invacuo several times gives 28 g. of solid. Column chromatography os thissolid on silica gel and recrystallization of the pure fractionscontaining the least polar component from acetone give 7.9 g. ofcolorless crystals m.p. 215.5°-218° C.

EXAMPLE 7 Preparation of N² -2-adamantyl-N⁴,N⁶-bis(1,1,2,2-tetramethylpropyl)melamine

Seven grams (0.02 mole) of2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine, 7.7 g.(0.041 mole) of 2-adamantylamine hydrochloride, 11 ml. (0.061 mole) ofN,N-diisopropylethylamine and xylene are refluxed under an argonatmosphere for 20 hours. After cooling, the reaction is diluted withethyl acetate and water. The mixture is then washed with water, theorganic phase dried over magnesium sulphate, filtered throughdiatomaceous earth and evaporated in vacuo to give a pale yellow solid,11 g. This solid is then dissolved in dichloromethane and filteredthrough Magnesol®. Evaporation of the solvent in vacuo andrecrystallization from n-heptane gives 3.0 g. of colorless crystals,m.p. 244°-249° C.

EXAMPLE 8 Preparation of exo-N² -2-norbornyl-N⁴,N⁶-bis[(1,1,2,2-tetramethylpropyl)amino]-melamine

Seven grams (0.02 mole) of2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine and 24 ml.(0.2 mole) of exo-2-norbornylamine is placed in a glass liner in a bomband then heated in an oil bath maintained at 185°-195° C. for 19-20hours. After cooling, the contents of the bomb are rinsed withchloroform and water into a flask and 50 ml. of 10N NaOH is added. Thesolution is then evaporated in vacuo and the aqueous solution remainingis extracted with chloroform. The combined chloroform extracts arewashed with water, dried over magnesium sulfate, filtered throughMagnesol® and the Magnesol® washed with chloroform. Removal of solventin vacuo and recrystallization from acetone gives 7 g. of colorlesscrystals, m.p. 159°-163° C.

We claim:
 1. The method of inhibiting the progression of arthritis in amammal which comprises administering to said mammal an effective amountof a compound selected from the group consisting of those of theformula: ##STR7## wherein R₁ is alkylamino having from 4 to 8 carbonatoms, inclusive, 1-adamantylamino,2-adamantylamino,exo[2.2.1]norbornylamino or endo[2.2.1]norbornylamino;R₂ is 1-adamantylamino, 2-adamantylamino, exo[2.2.1]norbornylamino orendo[2.2.1]norbornylamino; R₃ is hydrogen or alkyl having from 1 to 4carbon atoms, inclusive; R₄ is 2-(2-pyridyl)ethyl, alkyl having from 4to 8 carbon atoms, inclusive, phenyl, monohalo(F, Cl, Br)phenyl,1-adamantyl, 2-adamantyl, exo[2.2.1]norbornyl,endo[2.2.1]norbornyl or amonovalent moiety of the formula: ##STR8## wherein Q is a divalentmoiety of the formulae: ##STR9## R₅ is alkyl having up to 4 carbonatoms, R₆ is alkyl having up to 4 carbon atoms, and R₅ and R₆ takentogether with their associated N(itrogen) is piperidino, morpholino,pyrrolidino or thiomorpholino with the proviso that when R₄ is alkyladamantyl or norbornyl then R₃ must be hydrogen; and R₃ and R₄ takentogether with their associated N(itrogen) is pyrrolidino, piperidino,hexamethyleneimino, heptamethyleneimino or a monovalent moiety of theformula: ##STR10## wherein R is hydrogen, alkyl having up to 4 carbonatoms, phenyl, p-methoxyphenyl or carboalkoxy having up to 4 carbonatoms; and the non-toxic acid-addition and quaternary ammonium saltsthereof.
 2. The method of inhibiting the progressive joint deteriorationin a mammal which comprises administering to said mammal an effectiveamount of a compound selected from the group consisting of those of theformula: ##STR11## wherein R₁ is alkylamino having from 4 to 8 carbonatoms, inclusive, 1-adamantylamino,2-adamantylamino,exo[2.2.1]norbornylamino or endo[2.2.1]norbornylamino;R₂ is 1-adamantylamino, 2-adamantylamino, exo[2.2.1]norbornylamino orendo[2.2.1]norbornylamino; R₃ is hydrogen or alkyl having from 1 to 4carbon atoms, inclusive; R₄ is 2-(2-pyridyl)ethyl, alkyl having from 4to 8 carbon atoms, inclusive, phenyl, monohalo(F, Cl, Br)phenyl,1-adamantyl, 2-adamantyl, exo[2.2.1]norbornyl, endo[2.2.1]norbornyl or amonovalent moiety of the formula: ##STR12## wherein Q is a divalentmoiety of the formulae: ##STR13## R₅ is alkyl having up to 4 carbonatoms, R₆ is alkyl having up to 4 carbon atoms, and R₅ and R₆ takentogether with their associated N(itrogen) is piperidino, morpholino,pyrrolidino or thiomorpholino with the proviso that when R₄ is alkyladamantyl or norbornyl then R₃ must be hydrogen; and R₃ and R₄ takentogether with their associated N(itrogen) is pyrrolidino, piperidino,hexamethyleneimino, heptamethyleneimino or a monovalent moiety of theformula: ##STR14## wherein R is hydrogen, alkyl having up to 4 carbonatoms, phenyl, p-methoxyphenyl or carboalkoxy having up to 4 carbonatoms; and the non-toxic acid-addition and quaternary ammonium saltsthereof.
 3. The method of meliorating inflammation in a mammal whichcomprises administering to said mammal an effective amount of a compoundselected from the group consisting of those of the formula: ##STR15##wherein R₁ is alkylamino having from 4 to 8 carbon atoms, inclusive,1-adamantylamino, 2-adamantylamino,exo[2.2.1]norbornylamino orendo[2.2.1]norbornylamino; R₂ is 1-adamantylamino, 2-adamantylamino,exo[2.2.1]norbornylamino or endo[2.2.1]norbornylamino; R₃ is hydrogen oralkyl having from 1 to 4 carbon atoms, inclusive; R₄ is2-(2-pyridyl)ethyl, alkyl having from 4 to 8 carbon atoms, inclusive,phenyl, monohalo(F, Cl, Br)phenyl, 1-adamantyl, 2-adamantyl,exo[2.2.1]norbornyl,endo[2.2.1]norbornyl or a monovalent moiety of theformula: ##STR16## wherein Q is a divalent moiety of the formulae:##STR17## R₅ is alkyl having up to 4 carbon atoms, R₆ is alkyl having upto 4 carbon atoms, and R₅ and R₆ taken together with their associatedN(itrogen) is piperidino, morpholino, pyrrolidino or thiomorpholino withthe proviso that when R₄ is alkyl adamantyl or norbornyl then R₃ must behydrogen; and R₃ and R₄ taken together with their associated N(itrogen)is pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino or amonovalent moiety of the formula: ##STR18## wherein R is hydrogen, alkylhaving up to 4 carbon atoms, phenyl, p-methoxyphenyl or carboalkoxyhaving up to 4 carbon atoms; and the non-toxic acid-addition andquaternary ammonium salts thereof.